Stoichiometry of the Interaction between the Major Histocompatibility Complex-Related Fc Receptor and Its Fc Ligand

Sánchez, Luis Maria Bonnecarrère; Penny, David M.; Björkman, Pamela J.

doi:10.1021/bi9907330

Cited by 66 publications

(64 citation statements)

References 26 publications

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“…This is likely because of the increased avidity effects of the dimer, but may also be a requirement for inhibition of the IgG-FcRn complex in vivo. IgG contains two FcRn-binding sites and binds to FcRn in a 2:1 stoichiometry as observed for rat FcRn in solution (23) and by x-ray crystallography (37). More recently, hFcRn dimers have been reported on cell membranes (24).…”

Section: Discussionmentioning

confidence: 85%

“…More recently, hFcRn dimers have been reported on cell membranes (24). It has been suggested that this 2:1 stoichiometry may be a critical aspect of FcRn function (23), and therefore, a dimeric ligand for FcRn may best inhibit FcRn function in vivo. Thus, the lack of activity of monomeric SYN1327 in vivo may be due to its weaker affinity for FcRn or its monovalency.…”

Section: Discussionmentioning

confidence: 99%

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Reduction of IgG in nonhuman primates by a peptide antagonist of the neonatal Fc receptor FcRn

Mezo

McDonnell

Hehir

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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The neonatal Fc receptor FcRn provides IgG molecules with their characteristically long half-lives in vivo by protecting them from intracellular catabolism and then returning them to the extracellular space. Other investigators have demonstrated that mice lacking FcRn are protected from induction of various autoimmune diseases, presumably because of the accelerated catabolism of pathogenic IgGs in the animals. Therefore, targeting FcRn with a specific inhibitor may represent a unique approach for the treatment of autoimmune disease or other diseases where the reduction of pathogenic IgG will have a therapeutic benefit. Using phage display peptide libraries, we screened for ligands that bound to human FcRn (hFcRn) and discovered a consensus peptide sequence that binds to hFcRn and inhibits the binding of human IgG (hIgG) in vitro. Chemical optimization of the phage-identified sequences yielded the 26-amino acid peptide dimer SYN1436, which is capable of potent in vitro inhibition of the hIgG-hFcRn interaction. Administration of SYN1436 to mice transgenic for hFcRn induced an increase in the rate of catabolism of hIgG in a dose-dependent manner. Treatment of cynomolgus monkeys with SYN1436 led to a reduction of IgG by up to 80% without reducing serum albumin levels that also binds to FcRn. SYN1436 and related peptides thus represent a previously uncharacterized family of potential therapeutic agents for the treatment of humorally mediated autoimmune and other diseases.FcRn antagonist ͉ protein-protein interactions ͉ phage display ͉ autoimmune disease

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Reduction of IgG in nonhuman primates by a peptide antagonist of the neonatal Fc receptor FcRn

Mezo

McDonnell

Hehir

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…In the cocrystals, a long, repeating oligomeric ribbon with a 2n:n stoichiometry was observed, in which FcRn dimers are bridged by Fc molecules so that every Fc dimer interacts with two receptors (38). Studies also suggested that the 2:1 FcRn-Fc complex is formed in solution, although FcRn is not capable of dimerization in these conditions (28,29). However, in some studies, 1:1 FcRn/Fc stoichiometry was also observed under non-equilibrium conditions (27,29).…”

Section: Discussionmentioning

confidence: 99%

“…Several experiments showed a 2:1 FcRn/Fc binding stoichiometry (26,28,29), whereas the 1:1 FcRn-Fc complex was also observed in some studies (27,29). A better understanding of these interactions could be helped by generating and using monomeric Fc (mFc).…”

mentioning

confidence: 99%

Soluble Monomeric IgG1 Fc

Ying

Chen

Gong

et al. 2012

Journal of Biological Chemistry

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“…Crystal structures of IgG complexes with Fc␥RIII and of IgE with Fc⑀RI show 1:1 receptor:antibody stoichiometry, with the receptor binding across both heavy chains in the lower hinge (12). In contrast, the crystal structure of Fc␣RI complexed with IgA shows 2:1 stoichiometry (13) as does that of FcRn with IgG (14), with the two receptors binding between the heavy chain constant domains 2 and 3 on each heavy chain. The IgY/receptor interaction could have either stoichiometry; on the one hand, IgY is an orthologue of IgG and IgE, which can both show 1:1 stoichiometry, but on the other hand, the location of the IgY receptor, CHIR-AB1, in the same gene cluster as the IgA and FcRn receptors suggests the possibility of a 2:1 stoichiometry.…”

mentioning

confidence: 99%

A Monomeric Chicken IgY Receptor Binds IgY with 2:1 Stoichiometry

Taylor

Beavil

Sutton

et al. 2009

Journal of Biological Chemistry

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Fc receptors link the specificity of the adaptive immune system with the effector mechanisms of innate immune cells. In birds and reptiles, IgY is the principal serum antibody, and both mammalian IgG and IgE have evolved from an IgY-like ancestor, so studies of IgY offer insights into their origins (1). The historical contribution of chicken immunology to a wider understanding of the subject has been considerable (2), and recently several chicken IgY-Fc receptors have been identified. In this paper, the chicken antibody, IgY, is shown to bind to a chicken leukocyte receptor, CHIR-AB1, 4 in a different manner from that of its mammalian orthologues, IgG and IgE, to their respective Fc receptors. Phagocytosis, mediated in mammals by IgG, and passive cutaneous anaphylaxis, mediated by both IgG and IgE in mammals, have been observed in chickens (3, 4), presumably both effected by IgY. In vitro, IgY binds to monocyte cell lines (5, 6), and an IgY receptor (CHIR-AB1) has been identified that is able to mediate the influx of calcium into cells (5).The genes for the mammalian high affinity IgE receptor, and several IgG receptors, are located in the classical Fc receptor cluster, whereas in chickens, this cluster is represented by a single gene, the product of which has been expressed and found not to bind IgY (7). Intriguingly, the first IgY leukocyte receptor, CHIR-AB1, was found to be a member of the chicken leukocyte receptor cluster (LRC) (5), adjacent to over 100 genes with high intersequence homology (8). This finding, together with phylogenetic analysis of the orthologous Fc receptor gene clusters (7, 9), implies that during the evolution of the IgY-like ancestor of both IgG and IgE, antibody-Fc binding function migrated from proteins expressed in the LRC to those in the classical Fc receptor cluster. The human LRC is the site of Fc␣RI, the leukocyte receptor for IgA (an antibody involved in mucosal immunity), the fetal IgG receptor (FcRn, involved in adult IgG homeostasis), and also a number of natural killer cell receptors including the HLA-G ligand, KIR2DL4 (10). A further leukocyte receptor for chicken IgY, also related to LRC receptors, was identified recently, on chromosome 20 (11), and remains to be characterized.Typically, the stoichiometry of the receptor-antibody complex differs for receptors located in the classical Fc receptor cluster and the LRC. Crystal structures of IgG complexes with Fc␥RIII and of IgE with Fc⑀RI show 1:1 receptor:antibody stoichiometry, with the receptor binding across both heavy chains in the lower hinge (12). In contrast, the crystal structure of Fc␣RI complexed with IgA shows 2:1 stoichiometry (13)

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Stoichiometry of the Interaction between the Major Histocompatibility Complex-Related Fc Receptor and Its Fc Ligand

Abstract: The neonatal Fc receptor (FcRn) transports immunoglobulin G (IgG) across epithelia, providing passive immunity and protecting serum IgG from degradation. For both functions, FcRn binds to IgG at the acidic pH of intracellular vesicles (pH Show more

Cited by 66 publications

References 26 publications

Reduction of IgG in nonhuman primates by a peptide antagonist of the neonatal Fc receptor FcRn

Reduction of IgG in nonhuman primates by a peptide antagonist of the neonatal Fc receptor FcRn

Soluble Monomeric IgG1 Fc

A Monomeric Chicken IgY Receptor Binds IgY with 2:1 Stoichiometry

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